Cardiac Ischemia
Cardiac ischemia arises when the blood flow inside a coronary artery is restricted. The restricted blood flow is most commonly caused by plaque build-up on the inner walls or lining of the artery. Unable to obtain optimal amounts of oxygen and nutrients because of the reduced blood flow, cardiomyocytes function at sub-optimal levels and may die. The heart eventually is not able to pump blood efficiently. Episodes of cardiac ischemia can cause abnormal heart rhythms (arrhythmias), which can lead to either fainting or cardiac arrest and sudden cardiac death. Weakening of the heart muscle (cardiomyopathy) may also result. When a blood clot completely obstructs blood flow through an artery already narrowed by plaque, a heart attack may occur.
A number of options for treating cardiac ischemia are available. Some are based on reducing the heart's need for oxygen commensurate to the reduction in oxygen and nutrients that the heart receives because of reduced blood flow. These treatment options involve taking medications that slow the heart rate, reduce blood pressure, and relax the blood vessels. Such medications include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers block the effects of adrenaline on the body's beta receptors. As a result, the heart does not have to work as hard because it needs less blood and oxygen. Calcium channel blockers block the movement of calcium ions into heart cells, thus relaxing and dilating the arteries. By this mechanism, calcium channel blockers lower blood pressure. Nitrate medicines, including glyceryl trinitrate (GTN), isosorbide dinitrate, and isosorbide mononitrate, also relax and dilate the coronary arteries. Other medications, like aspirin and other antiplatelet agents, may decrease the chance of blood clot formation in an already narrowed artery. Exercise and/or stress management techniques are also recommended. More invasive procedures, such as balloon angioplasty or bypass surgery, may be used to clear the blockage in the coronary arteries. Drug-coated stents may reduce the rates of re-narrowing (restenosis) of the arteries following angioplasty.
Gene therapy is showing promise as an option to improve blood supply to the heart and relieve angina in patients with cardiac ischemia. In the area of therapeutic angiogenesis, experimental treatments that promote creation of new blood vessels are being developed. Injection of Ad5FGF-4, a replication-deficient serotype 5 adenovirus containing the gene for fibroblast growth factor-4, has been found to improve ischemic areas of the heart, with significant numbers of patients reporting relief of symptoms of angina (Grines et al., J. Am. Coll. Cardiol. (2003) 42:1339-1347; Grines et al., Am. J. Cardiol. (2003) 92:24 N-31N). However, the concept of introducing a growth factor gene into the heart and the potential for the introduced gene to do harm has raised concern.
Ischemic Cardiac Injury
Ischemic cardiac injury is sustained by the myocardium as a result of cardiac ischemia. At the cellular level, ischemic cardiac injury is characterized by a central region of cellular necrosis, surrounded by a penumbra or “volume at risk” (VAR) where cells typically undergo a delayed death. A substantial portion of cardiomyocyte loss after myocardial infarction and reperfusion has been shown to arise from apoptosis within this region. In addition, further injury occurs as a result of recruiting inflammatory cells into the infarcted region. The inflammatory cells release chemotactic and cytotoxic cytokines and other inflammatory molecules, thus expanding the volume of injury (Calvillo et al., Proc. Natl. Acad. Sci. USA (2003) 100:4802-4806). These forms of cell death and injury eventually may lead to heart failure.
Changes in gene expression after ischemia have been observed. Using a cDNA array approach, Lyn et al., Physiol. Genomics (2000) 2:93-100 showed that myocardial ischemia induced transcription of the apoptosis regulator BAX gene, the early growth response factor Egr-1 and Egr-3 genes, and genes associated with cardiac muscle development such as those encoding α-myosin heavy chain (α-MHC) and fetal myosin alkali light chain (MLC). Glutathione S-transferase gene transcription, on the other hand, decreased in response to ischemia.
There is currently no available therapy that replaces lost cardiomyocytes, aside from heart transplantation, which has obvious risks, limitations, and disadvantages. Heart transplantation is able to resolve the problems of heart failure and relieve patients' symptoms, but its utility is severely limited by suitable donor organ availability and problems of organ rejection (Lovell and Mathur, Cell Prolif. (2004) 37:67-87). Further, the ability of pharmacological agents to improve cardiac function to date is limited as these agents do not address the fundamental issue of cell loss. There thus remains a need for alternative treatment options for ischemic cardiac injury.
Congestive Heart Failure
Congestive heart failure is a consequence of most serious cardiac conditions. This pathological state is characterized by abnormal myocardial function, which causes the heart to fail to pump blood at a rate commensurate with the needs of the metabolizing tissues. It can result from primary damage to the heart muscle or secondary damage to the heart muscle due to a chronically excessive workload. In either case, the basis of congestive heart failure is defective myocardial contraction.
Treating cardiac ischemia, the resulting injury, and other cardiac conditions, such as congestive heart failure, remains a major public health challenge in the industrialized world. Cardiac conditions are a complication of atherosclerosis, which is a major cause of death and disability in industrialized nations. Therapies that prevent cardiomyocyte death or replace dead cardiomyocytes are currently severely limited. Treatments based on stem cell transplantation and gene transfer are still being investigated (Dawn et al., Proc. Natl. Acad. Sci. (2005) 102(10):3766-3771; Mariani et al., Ital. Heart J. (2004) 5:340-342; Matsui & Rosenzweig, Curr. Atheroscler. Rep. (2003) 5:191-195). Treatments based on delivery of growth factors have not yet overcome the potential side effect of growth factor-induced tumorigenesis. Methods that effectively cure heart failure by restoring the function of injured cardiomyocytes, or by stimulating myocardial cells to proliferate or differentiate in a way that improves cardiac function, are yet to be established. Accordingly, there remains a need to develop new methods, compositions, and agents for treating heart conditions.